The transparency of the lens, a feature of the eye that is integral to proper vision, is made possible by the high degree of organization and unique constitution of the lens fiber cells. Interruption in the arrangement of these cells impedes light transmission to the retina and results in cataracts. However, little is known on the regulation of these cells. We have recently observed that members of the Eph family of receptor kinases play a role in lens fiber cell organization. Our preliminary findings have indicated that inactivation of the Eph ligand ephrin-A5 results in the mislocalization of the adherens junction protein N-cadherin, alterations in lens fiber cell shape, and disruptions in lens cells organization, ultimately leading to cataracts. We hypothesize that ephrin-A5 interacts with its respective Eph receptor to regulate N-cadherin-mediated cell-cell adhesion, maintaining proper lens fiber cell organization. We first plan to test this hypothesis by defining the morphological changes between wild-type and ephrin-A5 null lenses in regards to age. Secondly, we will identify the Eph receptor in the lens that interacts with ephrin-A5 by examining which Eph receptors are located in the lens and determining whether the identified receptors are capable of being activated by ephrin-A5. Finally, we will identify the molecular mechanisms leading to cataracts as a result of the absence of ephrin-A5, looking specifically at the regulation of the N-cadherin adhesion complex. The proposed studies will critically analyze the role of a previously unsuspected family of molecules in lens development and maintenance, as well as uncover a novel regulation of N-cadherin adhesion. Understanding the mechanisms of Eph regulation will also further our knowledge of the mechanisms involved with lens transparency. Relevance to Public Health: Cataracts are a leading cause of blindness, affecting millions of individuals. However, many of the molecular mechanisms leading to the formation of this debilitating condition remain incompletely understood. The proposed experiments will study how the absence of the signaling molecule ephrin-A5 leads to cataracts, providing insight into future treatment and prevention of human cataracts. [unreadable] [unreadable] [unreadable]